A3 Adenosine Receptors Cardioprotective Mechanisms

A3 腺苷受体的心脏保护机制

• 批准号: 7195826
• 负责人: JOHN A AUCHAMPACH
• 金额: $ 11.56万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195826
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATP Synthesis Pathway; Acute; Adenosine; Adenosine A3 Receptor; Agonist; Apoptosis; Bioenergetics; Biological Preservation; Canis familiaris; Cardiac; Cardiac Myocytes; Caspase; Cells; Cysteine; Cytokine Signaling; DNA Fragmentation; Dose; Free Radical Scavengers; Functional disorder; Generations; Glycine; Goals; Heart; In Situ Nick-End Labeling; Infarction; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Ischemic Preconditioning; Knockout Mice; Lactate Dehydrogenase; Left; Magnetic Resonance Spectroscopy; Measurement; Mediating; Membrane Potentials; Metabolic; Mitochondria; Modeling; Mus; Myocardial Ischemia; N(6)-(3-iodobenzyl)-5' -N-methylcarboxamidoadenosine; NF-kappa B; Necrosis; Neutrophil Infiltration; Pathogenesis; Pathway interactions; Patients; Peptides; Phosphotransferases; Physiologic intraventricular pressure; Physiological reperfusion; Play; Potassium; Preparation; Production; Protein Isoforms; Protein Kinase; Protein Kinase C; Purinergic P1 Receptors; Rate; Reactive Oxygen Species; Receptor Gene; Receptor Signaling; Reperfusion Injury; Reperfusion Therapy; Research; Respiration; Role; Signal Pathway; Signal Transduction; Specificity; Staining method; Stains; Testing; Therapeutic; Time; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; attenuation; channel blockers; chelerythrine; clinically relevant; concept; cytokine; hemodynamics; human TNF protein; in vivo; inhibitor/antagonist; inorganic phosphate; insight; mitochondrial membrane; myocardial infarct sizing; nuclear factor 1; protein kinase C epsilon; research study; rottlerin; size; sodium 5-hydroxydecanoate

DESCRIPTION (provided by applicant): The goal of this research is to define the mechanisms by which A3 adenosine receptors (ARs) protect against myocardial ischemia/reperfusion injury. We will test the hypothesis that A3ARs are protective by multiple mechanisms including preservation of mitochondrial function, reduction of apoptosis, and attenuation of inflammation. We predict that the A3AR signals via kinase signaling pathways that ultimately results in protection by activation of mitochondrial KATP channels. A key feature of our hypothesis is that we predict that A3ARs are expressed in cardiac myocytes. We will test these hypotheses by examining the effect of selective A3AR agonists in an isolated mouse heart model of global ischemia/reperfusion and a clinically relevant in vivo dog model of infarction. The isolated mouse heart model will be used to correlate post-ischemic contractile function (left ventricular pressure) and cell necrosis (LDH released) with metabolic state (high-energy phosphates), mitochondrial integrity (mitochondrial membrane potential, respiration, and rate of ATP synthesis), apoptosis (DNA fragmentation, TUNEL staining, caspase activation), and pro-inflammatory cytokine signaling (NF kappa B activation, TNF alpha production). The in vivo dog model of infarction will be used to compare infarct size with markers of inflammation (neutrophil infiltration). The mitochondrial specific KATP channel blocker sodium 5-hydroxydecanoate will be used to delineate the role of mitochondrial KATP channels in preserving mitochondrial and cardiac function. Experiments will be performed to determine whether A3ARs signal via specific protein kinases (PKC-epsilon or delta; PI-3/akt kinase) and/or generation of reactive oxygen species. Information obtained from these studies will advance the understanding of the fundamental questions involved in cellular protection. The results of theses studies should also provide new insights into the therapeutic utility of targeting A3ARs in patients with ischemic heart disease.

描述（由申请人提供）：本研究的目的是确定 A3 腺苷受体 (AR) 防止心肌缺血/再灌注损伤的机制。 我们将检验 A3AR 通过多种机制提供保护的假设，包括保存线粒体功能、减少细胞凋亡和减轻炎症。 我们预测 A3AR 通过激酶信号通路发出信号，最终通过激活线粒体 KATP 通道产生保护。 我们假设的一个关键特征是我们预测 A3AR 在心肌细胞中表达。 我们将通过检查选择性 A3AR 激动剂在离体小鼠整体缺血/再灌注心脏模型和临床相关的狗体内梗塞模型中的作用来检验这些假设。 离体小鼠心脏模型将用于将缺血后收缩功能（左心室压力）和细胞坏死（LDH 释放）与代谢状态（高能磷酸盐）、线粒体完整性（线粒体膜电位、呼吸和 ATP 速率）相关联合成）、细胞凋亡（DNA 片段化、TUNEL 染色、半胱天冬酶激活）和促炎细胞因子信号传导（NF kappa B 激活、TNF α 产生）。 犬体内梗塞模型将用于将梗塞大小与炎症标志物（中性粒细胞浸润）进行比较。 线粒体特异性 KATP 通道阻滞剂 5-羟基癸酸钠将用于描述线粒体 KATP 通道在保护线粒体和心脏功能中的作用。 将进行实验以确定 A3AR 是否通过特定蛋白激酶（PKC-ε 或 δ；PI-3/akt 激酶）发出信号和/或产生活性氧。 从这些研究中获得的信息将促进对细胞保护所涉及的基本问题的理解。 这些研究的结果还应该为针对缺血性心脏病患者靶向 A3AR 的治疗效用提供新的见解。

项目成果

Reperfusion injury: Does it exist?

• DOI: 10.1016/j.yjmcc.2006.09.009
• 发表时间: 2007-01-01
• 期刊: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
• 影响因子: 5
• 作者: Gross, Garrett J.;Auchampach, John A.
• 通讯作者: Auchampach, John A.

Comparison of cardioprotective efficacy of two thromboxane A2 receptor antagonists.

两种血栓素 A2 受体拮抗剂的心脏保护功效比较。

• DOI: 10.1097/00005344-200303000-00018
• 发表时间: 2003
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Ge,Zhi-Dong;Auchampach,JohnA;Piper,GalenM;Gross,GarrettJ
• 通讯作者: Gross,GarrettJ

Characterization of a critical role for CFTR chloride channels in cardioprotection against ischemia/reperfusion injury.

• DOI: 10.1038/aps.2011.61
• 发表时间: 2011-06
• 期刊: ACTA PHARMACOLOGICA SINICA
• 影响因子: 8.2
• 作者: Xiang, Sunny Yang;Ye, Linda L.;Duan, Li-lu Marie;Liu, Li-hui;Ge, Zhi-dong;Auchampach, John A.;Gross, Garrett J.;Duan, Dayue Darrel
• 通讯作者: Duan, Dayue Darrel